In a new study, researchers aimed to identify and validate predictive biomarkers of response to neoadjuvant chemotherapy (NAC) in patients with muscle-invasive bladder cancer (MIBC).
Neoadjuvant chemotherapy (NAC) is a type of cancer treatment involving the administration of chemotherapy drugs before surgery. The goal of NAC is to shrink the tumor(s) in order to make it/them easier to remove during surgery and to decrease the chance of cancer recurrence after treatment. NAC is typically well tolerated by patients and has been shown to improve outcomes in patients with bladder cancer.
Predictive biomarkers are being increasingly used in oncology to identify patients who are likely to respond to chemotherapy. In the past, the decision to administer chemotherapy was based on tumor type and stage. However, it is now understood that there is considerable heterogeneity within these groups, and that not all patients will respond to the same treatment. Predictive biomarkers can help to overcome this challenge by identifying those patients who are most likely to benefit from chemotherapy.
There are a number of different types of predictive biomarkers, which can be divided into two broad categories: tumor biomarkers and host biomarkers. Tumor biomarkers are usually specific to the tumor type and can include markers of cell proliferation and DNA repair. Host biomarkers are usually found in the blood or other bodily fluids and can include markers of inflammation, immune function and metabolism. The use of predictive biomarkers has the potential to improve the efficacy of chemotherapy and reduce toxicity by avoiding its use in patients who are unlikely to benefit.
The Study
In a new study, researchers Neal Murphy, Andrew J. Shih, Paras Shah, Oksana Yaskiv, Houman Khalili, Anthony Liew, Annette T. Lee, and Xin-Hua Zhu from Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Northwell Health Cancer Institute, Feinstein Institutes for Medical Research, and Mayo Clinic aimed to develop and validate a predictive biomarker panel for response to NAC in patients with muscle-invasive bladder cancer (MIBC). Their research paper was published on November 2, 2022, in Oncotarget’s Volume 13, entitled, “Predictive molecular biomarkers for determining neoadjuvant chemosensitivity in muscle invasive bladder cancer.”
“The NAC non-responders suffer from unnecessary adverse effects and a delay in time to cystectomy leading to worse overall survival [9, 10]. Subsequently, there remains a critical need to understand the molecular biology behind NAC responsiveness, in order to better tailor individual NAC therapy.”
The purpose of this research was to “develop a molecular signature that can identify MIBC NAC responders (R) and non-responders (NR) using a cohort of known NAC response phenotypes, and better understand differences in molecular pathways and subtype classifications between NAC R and NR.” Researchers identified a total of 26 patients with known NAC response for inclusion in this study. These patients were assigned at random to either the discovery or validation cohort. The discovery cohort consisted of seven NAC responders and 11 non-responders. The validation cohort consisted of three responders and five non-responders.
Transurethral resection of bladder tumor (TURBT) specimens from the Northwell Health pathology department were received as formalin-fixed, paraffin-embedded (FFPE) tissue blocks. Pathologic response was determined at the time of cystectomy. Messenger RNA (mRNA) and microRNA (miRNA) from the FFPE blocks were sequenced using RNAseq and qPCR, respectively.
“To our knowledge, our study is the first to use combined differential mRNA and miRNA expression in MIBC to identify a NAC response signature.”
The Results
“We report significant gene sets associated with NAC response phenotype, as well as three multigene and miRNA signatures generated by CCA that can be used to potentially classify NAC response.”
In the discovery cohort, the researchers found that 2309 genes were differentially expressed between the NAC responders and non-responders. In the validation cohort, 602 genes and 13 miRNA were differentially expressed. Canonical correlation (CC) analysis found that three CCs (CC13: nucleoside triphosphate metabolic process; CC16: cell cycle and cellular response to DNA damage; and CC17: DNA packaging complex) were differentiated in the discovery and validation datasets. As far as MIBC subtypes, the MD Anderson p53-like subtype, CIT MC4 subtype and Consensus Class stroma-rich subtype had the strongest correlation with a non-responder phenotype. There were no subtypes that had strong correlations with the responder phenotype.
“In conclusion, our results identify molecular signatures that can be used to differentiate MIBC NAC responders versus non-responders. We have presented the salient molecular pathways and relevant genes, including mitochondrial response gene expression (MRPS12, MRPS34, MRPS28, MRPS14, and MRPS2), DNA replication initiation, and DNA unwinding and DNA damage (MCM2-3, MCM5-6 and XAP , ELK4, and FOXA3) that can be further analyzed to better understand NAC response. The above mentioned genes derived from their respective three pathways may be selected as part of a NAC response biomarker panel. In addition, we have highlighted the utility of molecular subtyping in relation to NAC response. If validated in a larger cohort, these findings may help deliver chemotherapy to those patients most likely to respond.”
Conclusion
Neoadjuvant chemotherapy is a promising treatment option for muscle-invasive bladder cancer patients, however, there is a class of patients who do not respond to chemotherapy. The results of this study implicate several different types of biomarkers that may be associated with chemosensitivity in MIBC patients. Further research is needed to validate these findings. Ultimately, if validated, these biomarkers could help to spare non-responders from side effects associated with ineffective and unnecessary chemotherapy.
“Our results identify molecular signatures that can be used to differentiate MIBC NAC R versus NR, salient molecular pathway differences, and highlight the utility of molecular subtyping in relation to NAC response.”
Click here to read the full research paper published by Oncotarget.
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